Schizophrenia is a kind of psychiatric diseases which mostly occurs during puberty or adolescence, and its lifetime prevalence is as high as about 1% of the population. Its symptoms are classified into positive symptoms such as psychomotor excitation, hallucinations and delusions; negative symptoms such as loss of spontaneity, apathy and poor rapport; and cognitive deficiencies as discussed in Folia Pharmacol Jpn, 127, 4, 2006.
As a mechanism of pathogenesis of schizophrenia, the hypothesis of excessive dopamine in the brain has been proposed, so that, at present, a typical or atypical antipsychotics whose main pathway is direct blocking of dopamine receptors is used as a therapeutic agent for schizophrenia, which agent is comprehensively applied to the above-described 3 types of symptoms. However, since direct blocking of dopamine receptors may cause side effects such as extrapyramidal symptoms (EPS), a therapeutic agent having a different mode of action and a wide margin of safety is demanded.
As compounds which suppress dopamine release in the brain, opioid κ receptor agonists such as a morphinan compound (WO 99/011289), which is an effective ingredient, nalmefene (Gavin B et al., Neuropsychopharmacology, 30, 2554, 2005) and U-50,488H (Werling L L et al., J. Pharmacol. Exp. Ther., 246, 282, 1988) are known, and, among these, nalmefene, which has a morphinan skeleton in common with the compound, is reported to have actually exerted a therapeutic effect against schizophrenia (Rapaport M H et al., Neuropsychopharmacology, 9, 111, 1993). However, there is a large difference in structures and no suggestion of their having a therapeutic effect against schizophrenia.
Further, on the other hand, U-50,488H which is known to have an inhibitory action on dopamine release has been suggested to have a possibility of causing impaired information processing disorder leading to cognitive deficiencies or the like which is a symptom of schizophrenia (Marco B et al., Biol. Psychiatry, 57, 1550, 2005). However, although the inhibitory action of a specific morphinan compound on dopamine release has been disclosed, there is no suggestion in that publication that a therapeutic effect against schizophrenia is exhibited without causing a side effect such as cognitive deficiencies.
In addition to the above, a morphinan compound is described in WO 93/015081 together with its analgesic activity, diuresis activity, antitussive activity, and agonistic activity to opioid κ receptors.
Further, its uses as a protective agent for brain cells (WO 95/003307), antipruritic (WO 98/023290), therapeutic agent for hyponatremia (WO 99/005146), ORL-1 receptor antagonist (JP 2000-53572 A), therapeutic agent for neuropathic pain (WO 01/014383), therapeutic agent for psychoneurotic disorders (WO 02/078744), therapeutic agent for drug dependence (WO 99/011289), therapeutic agent for sepsis (WO 02/089845), therapeutic agent for pruritus caused by multiple sclerosis (WO 06/095836) and the like have already been disclosed. Among these, although WO 02/078744 discloses a therapeutic use for “psychoneurotic disorders”, only an effect against Restless Legs Syndrome (RLS) belonging to a neurological disorder has been disclosed, without disclosing a therapeutic effect against schizophrenia at all.
It could therefore be helpful to provide a therapeutic or prophylactic agent for schizophrenia having a remarkable effect, which therapeutic or prophylactic agent does not cause impaired information processing related to cognitive deficiencies which is a symptom of schizophrenia, and has fewer side effects.